Thioredoxin family active site proteins are a superfamily of proteins that participate in redox reactions and are distributed among a wide range of living organisms (Holmgren, A. (1985) Ann. Rev. Biochem. 54:237-271; Eklund, H. et al. (1991) Proteins 11:13-28; Freedman, R. B. et al. (1994) Trends in Biochem. Sci. 19:331-336). The thioredoxin family active site is characterized by a CXXC motif (C represents cysteine and X represents any of the 20 amino acids incorporated into proteins). The neighboring cysteine residues cycle between a reduced sulfhydryl and an oxidized disulfide form.
The reduced form of thioredoxin is known to activate some enzymes by reducing disulfide bridges that control their activity. In addition, thioredoxin is an electron donor in the reaction sequence that reduces ribonucleotides to deoxyribonucleotides catalyzed by ribonucleotide reductase (Stryer, L. (1995) Biochemistry 4th Edition, W.H. Freeman and Company, pages 677, and 750-751.). It has been reported that in humans, thioredoxin and the cellular redox state modified by thioredoxin play a crucial role in arterial neointima formation in atherosclerosis (Takagi, Y. et al. (1998) Laboratory Investigation 78:957-66). Thioredoxin is believed to be involved in cellular defense mechanisms against oxidative damage (see, for example, Tanaka, T. et al. (1997) Laboratory Investigation 77:145-55). Thioredoxin has also been implicated in regulating glucocorticoid responsiveness to cellular oxidative stress response pathways. In particular, thioredoxin is believed to be capable of sensing, and transmitting, the redox state of the cell, to the glucocorticoid receptor by targeting both the ligand- and DNA-binding domains of the receptor (Makino, Y. et al. (1996) Journal of Clinical Investigation 98:2469-77). Human thioredoxin has been suggested to act as a free radical scavenger and has been shown to limit the extent of ischaemia reperfusion injury (Fukuse, T. et al. (1995) Thorax 50:387-91).
Protein disulfide isomerases are an important class of thioredoxin family active site-containing proteins that catalyze the oxidation of thiols, reduction of disulfide bonds, and isomerization of disulfides, depending on the reaction conditions (Freedman, R. B. et al. (1994) Trends in Biochem. Sci. 19:331-336).
Protein disulfide isomerases catalyze the formation of correct disulfide pairings in nascent proteins. Protein disulfide isomerases preferentially interact with peptides that contain cysteine residues but are otherwise undiscriminating. The broad substrate specificity of protein disulfide isomerases enables them to speed the folding of diverse disulfide-containing proteins. By shuffling disulfide bonds, protein disulfide isomerases enable proteins to quickly find the most thermodynamically stable pairings amongst those that are accessible. Consequently, protein disulfide isomerases are involved in protein processing, protein folding, and protein secretion. Certain protein disulfide isomerases are also involved in collagen and collagen-like protein biosynthesis because a protein disulfide isomerase is a subunit of prolyl 4-hydroxylase, a collagen and collagen-like protein biosynthetic enzyme (Kivirikko, K. I. et al. (1998) Matrix Biol. 16:357-368; Kivirikko, K. I. et al. (1998) Adv. Enzymol. Relat. Areas Mol. Biol. 72:325-398). Because mutations in prolyl 4-hydroxylase cause Ehlers-Danlos Syndrome, protein disulfide isomerases have been implicated in Ehlers-Danlos Syndrome.
Given the important biological roles and properties of thioredoxin family active site-containing proteins, there exists a need for the identification of novel genes encoding such proteins as well as for the discovery of modulators of such molecules for use in regulating a variety of normal and/or pathological cellular processes.